Treatment of pemphigus

ABSTRACT

The present disclosure provides provides methods of treating with a BTK inhibitor a blistering disease, in particular pemphigus vulgaris or pemphigus folliaceous in a mammal, use of a BTK inhibitor as a replacement therapy for corticosteroid therapy for diseases treatable with a corticosteroid, such as autoimmune or inflammatory disease and in particular where corticosteroids are used as first or second line therapy, and pharmaceutical formulations comprising the same.

This application is continuation of U.S. application Ser. No.15/537,294, filed Jun. 16, 2017, which is a U.S. national phase entryunder 35 U.S.C. § 371 from PCT International Application No.PCT/US2015/066868, filed Dec. 18, 2015, which claims the benefit ofpriority to U.S. Provisional Application No. 62/093,891, filed Dec. 18,2014, the contents of each of which are incorporated by referenceherein.

The present disclosure provides methods of treating a blisteringdisease, in particular pemphigus vulgaris or pemphigus foliaceous with aBTK inhibitor in a mammal, use of a BTK inhibitor as a replacementtherapy for corticosteroid therapy for diseases treatable with acorticosteroid, such as autoimmune or inflammatory disease and inparticular where corticosteroids are used as first or second linetherapy, and pharmaceutical formulations comprising the same.

Pemphigus vulgaris (PV) is a tissue-specific autoimmune blisteringdisease of the skin and mucous membranes in humans (Scully C,Challacombe S. J. Pemphigus vulgaris: update on etiopathogenesis, oralmanifestations, and management. Crit Rev Oral Biol Med 2002; 13:397-408) and is associated with considerable risks of morbidity andmortality. PV patients exhibit severe mucosal erosions and epidermalblistering that rupture easily, leading to erosions and crusts.

The disease is characterized by deposition of immunoglobulin G (IgG) andblister formation just above the basal cell layer of the epidermis. PVis associated with and thought to be driven by autoantibodies againstthe adhesion molecules desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1),transmembrane proteins belonging to the cadherin family. Dsg3 and Dsg1play a role connecting cells in the stratified squamous epithelium.Antibodies against Dsg3 and Dsg1 as well as PV patient sera have beenassociated with disruption of desmosomal function and keratinocyteadhesion (Ugajin T, Yahara H, Moriyama Y, et al. Two siblings withneonatal pemphigus vulgaris associated with mild maternal disease. Br JDermatol 2007; 157 (1): 192-4). Anti-Dsg3 titres are correlated with thedisease activity, and reactivity to certain epitopes on Dsg3 arecorrelated with clinical phenotype or severity (Campo-Voegeli A.Neonatal pemphigus vulgaris with extensive mucocutaneous lesions from amother with oral pemphigus vulgaris. Br J Dermatol 2002: 147: 801-5).

At present the mainstay treatment for PV includes high doses of oral orparenteral corticosteroids either alone or in combination withimmunosuppressive drugs such as cyclophosphamide, mycophenolate mofetil,methotrexate, dapsone, sulfasalazine or azathioprine (Murrell D F,Autoimmune blistering diseases: Part II—diagnosis and management.Dermatol Clinics Vol 29, No 4, October 2011, Ribeiro A M, Alvarez R R,Friedman H, et al. The profile of fogo selvagem (endemic pemphigusfoliaceus) at the University Hospital of Brasilia-Brazil:epidemiological and clinical considerations. Int J Dermatol 2005 April;44 (4): 293-8). Optimization of these therapies is difficult andsignificant side effects of corticosteroids, such as weight gain withCushingoid features, hypertension, disturbances of glucose and calciummetabolism, myopathy, mood disorder, and sepsis, are experienced bypatients and contribute to the relatively high mortality in the firstyear of approximately 5% (Murrell D. F. AutoImmune Blistering DiseasePart I, An Issue of Dermatologic Clinics, 1st Edition, ISBN9781455710331).

Due to severe side effects associated with use of corticosteroid,alternative therapies to corticosteroids for the treatment in PV havebeen explored and some of them include use of (i) high dose intravenousimmunoglobulin (IVIG) administration when conventional immunosuppressivetherapies are not effective and (ii) anti-CD20 antibody rituximab, whichis approved for treatment of B cell malignancies and is increasing beingused to treat automimmune diseases (Esmaili N, Chams-Davatchi C,Valikhani M, et al. Pemphigus vulgaris in Iran: a clinical study of 140cases. Int J Dermatol 2007; 46: 1166-70; Mahoney M, Wang Z, RothenbergerK, et al. Explanations for the clinical and microscopic localization oflesions in pemphigus foliaceus and vulgaris. J Clin Invest 1999; 103:461-8).

The drawbacks of the above therapies is that the IVIG therapy isexpensive and has adverse effects such as headache, backache, flushing,fever, nausea and vomiting, anaphylaxis, aseptic meningitis, renalfailure, and hypertension (see Product Label) and rituximab hassignificant delay in clinical response (maximal effect at 8-12 weeks seeLundardon L & Payne A S G Ital Dermatol Venereol 2012; 147(3):269-276)requiring continued corticosteroid therapy for some months andfurthermore the durability of the response as measured byanti-keritinocyte antibodies are varied ranging between no relapse tomultiple relapses. In addition, patients treated with rituximab sufferedserious side effects such as pneumonia (see Morrison L. H. Therapy ofrefractory pemphigus vulgaris with monoclonal anti-CD20 antibody(rituximab) J Am Acad Dermatol 2004; 51:817-819 and Dupuy A, et. al.Treatment of refractory pemphigus vulgaris with rituximab (anti-CD20monoclonal antibody) Arch Dermatol. 2004; 140:91-96), neutropenia (seeRios-Femandez R. et al. Late-onset neutropenia following rituximabtreatment in patients with autoimmune disease Br J. Detmatol. 2007;157:1271-1273 and Goh M. S et al. Rituximab in the adjuvant treatment ofpemphigus vulgaris: a prospective open-label pilot study in fivepatients. Br J. Dermatol. 2007:156: 990-996), DVT and pulmonary embolism(Shimanovich I, et. al. Treatment of severe pemphigus with protein Aimmunoadsorption, rituximab and intravenous immunoglobulins Br J.Dermatol 2008; 158:382-388) including death from septic shock (TournadreA, et al. Polymyositis and pemphigus vulgaris in a patient successfultreatment with rituximab Jt Bone Spine 2008:75:728-729). Accordingly,there is a need for new therapies that can treat PV effectively andrelated diseases without causing or at least reducing serious sideeffects compared to the standard of care in treating pemphigus.

In a recent study conducted by the Applicant in which a dog sufferingfrom pemphigus foliaceus (PF) was administered(R,E)-2-(3-(4-amino-3-(2-fluoro-4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile,a Bruton Tyrosine Kinase (BTK) inhibitor, as a single agent, it wassurprisingly discovered that inhibition of BTK is effective and safe forthe treatment of PF.

In addition, it was surprisingly discovered that the manifestation ofclinical response with(R,E)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile,was as rapid and comparable to that observed with systemiccorticosteroid therapy. Additionally, none of the well-knowncorticosteroid-like adverse effects in canines, such as polyuria,polydipsia, polyphagia or weight gain, was observed.

Accordingly, the present disclosure provides methods of treating ablistering disease, such as pemphigus vulgaris (PV) or pemphigusfoliaceous (PF) with a BTK inhibitor in a mammal, use of a BTK inhibitoras a replacement therapy for corticosteroid therapy for diseasestreatable with a corticosteroid (such as autoimmune or inflammatorydisease and in particular where corticosteroids are used as first orsecond line therapy), where a rapid clinical response is desirable.Also, disclosed are methods of treating autoimmune and/or inflammatorydiseases with a BTK inhibitor at a specific phase of the disease process(such as acute phase and/or at onset and duration of an acute flare) andfor a limited amount of time so as to maximize short term relief,minimize long term progression of the disease, and minimize long termtoxicological and other adverse effects.

FIG. 1A shows the nose of a 30 kg Doberman dog with a characteristicfirst presentation of pemphigus foliaceous on the nose and paws prior totreatment with a BTK inhibitor. FIG. 1B depicts the same dog's nosetwenty-eight days after treatment.

FIG. 2A shows the feet pads of a 30 kg Doberman dog with acharacteristic first presentation of pemphigus foliaceous on the noseand paws prior to treatment with a BTK inhibitor. FIG. 2B depicts thesame dog's feet pads twenty-eight days after treatment.

Accordingly, in a first aspect, provided is a method of treating anautoimmune blistering disease in a mammal in need thereof which methodcomprises administering to the mammal in need of said treatment atherapeutically effective amount of a BTK inhibitor.

In a second aspect, provided is a method of treating an acuteinflammatory and/or autoimmune disease in a mammal in need thereof wherecorticosteroid therapy is used as the first or second line therapycomprising administering to said mammal in need of said treatment atherapeutically effective amount of a BTK inhibitor in place of or incombination with said corticosteroid therapy; and

optionally administering said BTK inhibitor in combination with anoncorticosteroidal immunosupressive and/or antiinflammatory agents.

In a third aspect, provided is a method of treating an inflammatoryand/or autoimmune disease in a mammal in need thereof wherecorticosteroid therapy is used as the first or second line maintenancetherapy comprising administering to said mammal in need of saidtreatment a therapeutically effective amount of a BTK inhibitor in placeof or in combination with said corticosteroid therapy; and

optionally administering said BTK inhibitor in combination with anoncorticosteroidal immunosupressive and/or antiinflammatory agent.

In a fourth aspect, provided is a method of eliminating or reducing atherapeutic dose of corticosteroid used in chronic maintenance therapyof an inflammatory and/or autoimmune disease in a mammal in need thereofwhere corticosteroid therapy is used as the first or second linecomprising administering to said mammal in need of said treatment atherapeutically effective amount of a BTK inhibitor in place of or incombination with said corticosteroid chronic maintenance therapy; and

optionally administering said BTK inhibitor in combination with anoncorticosteroidal, immunosupressive, and/or antiinflammatory agents.

In a fifth aspect, provided is a method of treating acute flares of anautoimmune and/or inflammatory disease in a mammal in need thereof whichmethod comprises administering to the mammal in need of said treatment atherapeutically effective amount of a BTK inhibitor for a treatmentperiod sufficient to treat acute flares of the autoimmune disease. Inone embodiment of the fifth aspect, the BTK inhibitor is used instead ofcorticosteroid therapy where corticosteroid therapy is normally used asthe first or second line to treat flares.

In a first embodiment of the second and fifth aspects, the autoimmuneand/or inflammatory disease is chosen from Table (I):

TABLE (I) Acute indications for corticosteroid therapy Effects of B celltherapy if known Initial presentations or flares of rheumatic Rituximabtakes 4-12 weeks to take effect in disorders such as psoriaticarthritis, rheumatoid arthritis (ref Rituxan US label) rheumatoidarthritis, ankylosing spondylitis, bursitis, tenosynovitis, gout,synovitis of osteoarthritis, epicondylitis Initial presentation orflares of collagen Rituximab has delayed effect in ANCA- disease such assystemic lupus erythematosus associated vasculitis and achievesremission (SLE), dermato/polymyositis, rheumatic in only 64% of casesdespite concomitant use carditis, vasculitis of corticosteroids for 5months (Stone et al. 2010). Belimumab, an anti-Blys antibody, has amodest and delayed effect on improvement of chronic SLE including theability to reduce corticosteroid use to <7.5 mg of prednisone at week40-52 in no more than 21% of patients (Benlysta US Product Information).Initial presentations or flares of dermatologic Rituximab has delayedeffect in pemphigus diseases such as pemphigus, Stevens-Johnson vulgariswith maximal effect at 8-12 weeks syndrome, exfoliative dermatitis,mycosis (Lundardon & Payne 2012) fungoides, severe psoriasis, severeseborrheic dermatitis Control of incapacitating allergic reactionsincluding asthma, contact or atopic dermatitis, serum sickness, drughypersensitivity Initial presentations or flares of ophthalmic diseasesincluding allergic corneal ulcers, herpes zoster of the eye, anterior orposterior inflammation/uveitis or choroiditis, sympathetic ophthalmia,allergic conjunctivitis, keratitis, chorioretinitis, optic neuritis,iritis, iridocyclitis Initial presentations or flares of respiratorydiseases including symptomatic sarcoidosis, Loeffler's syndrome,berylliosis, fulminating or disseminated tuberculosis, aspirationpneumonitis Initial presentations or flares of hematologic disordersincluding idiopathic thrombocytopenic purpura, secondarythrombocytopenia, autoimmune hemolytic anemia, erythroblastopenia,congential hypoplastic anemia Acute nephrotic syndrome of SLE Initialpresentations or flares of gastrointestinal disease such as ulcerativecolitis, Crohn's disease Acute neurological trauma to reduce swelling

In a second embodiment of the first, second, third, fourth, and fifthaspects, the autoimmune and/or inflammatory disease is chosen from Table(II) below:

TABLE (II) Indications for Prednisone tablets Endocrine disorders:Primary or secondary adrenocortical insufficiency (hydrocortisone orcortisone is the first choice: synthetic analogs may be used inconjunction with mineralocorticoids where applicable; in infancymineralocorticoid supplementation is of particular importance).Congenital adrenal hyperplasia Nonsuppurative thyroiditis Hypercalcemiaassociated with cancer Rheumatic disorders: As adjunctive therapy forshort-term administration (to tide the patient over an acute episode orexacerbation) in: Psoriatic arthritis Rheumatoid arthritis, includingjuvenile rheumatoid arthritis (selected cases may require low-dosemaintenance therapy) Ankylosing spondylitis Acute and subacute bursitisAcute nonspecific tenosynovitis Acute gouty arthritis Post-traumaticosteoarthritis Synovitis of osteoarthritis Epicondylitis Collagendiseases: During an exacerbation or as maintenance therapy in selectedcases of: Systemic lupus erythematosus Systemic dermatomyositis(polymyositis) Acute rheumatic carditis Dermatologic diseases: PemphigusBullous dermatitis herpetiformis Severe erythema multiforme(Stevens-Johnson syndrome) Exfoliative dermatitis Mycosis fungoidesSevere psoriasis Severe seborrheic dermatitis Allergic states: Controlof severe or incapacitating allergic conditions intractable to adequatetrials of conventional treatment: Seasonal or perennial allergicrhinitis Serum sickness Bronchial asthma Contact dermatitis Atopicdermatitis Drug hypersensitivity reactions Ophthalmic diseases: Severeacute and chronic allergic and inflammatory processes involving the eyeand its adnexa, such as: Allergic conjunctivitis Keratitis Allergiccorneal marginal ulcers Herpes zoster ophthalmicus Iritis andiridocyclitis Chorioretinitis Anterior segment inflammation Diffuseposterior uveitis and choroiditis Optic neuritis Sympathetic ophthalmiaRespiratory diseases: Symptomatic sarcoidosis Loeffler's syndrome notmanageable by other means Berylliosis Fulminating or disseminatedpulmonary tuberculosis when used concurrently with appropriateantituberculous chemotherapy. Aspiration pneumonitis Hematologicdisorders: Idiopathic thrombocytopenic purpura in adults Secondarythrombocytopenia in adults Acquired (autoimmune) hemolytic anemiaEythroblastopenia (RBC anemia) Congenital (erythroid) hypoplastic anemiaNeoplastic diseases: For palliative management of: Leukemias andlymphomas in adults Acute leukemia of childhood Edematous states: Toinduce a diuresis or remission of proteinuria in the nephrotic syndrome,without uremia, of the idiopathic type or that due to lupuserythematosus. Gastrointestinal diseases: To tide the patient over acritical period of the disease in: Ulcerative colitis Regional enteritisNervous system: Acute exacerbations of multiple sclerosis Miscellaneous:Tuberculous meningitis with subarachnoid block or impending block whenused concurrently with appropriate antituberculous chemotherapy.Trichinosis with neurologic or myocardial involvement.

In a third embodiment of the first, second, third, fourth, and fifthaspects, the disease is pemphigus vulgaris (PG) or pemphigus foliaceus(PF). In a fourth embodiment of the first, second, third, fourth, andfifth aspects, and the first and second embodiments contained therein,the BTK inhibitor is administered as a monotherapy. In a fifthembodiment of the first, second, third, fourth, and fifth aspects, andthe first, second and third embodiments contained therein, the BTKinhibitor is administered in acute PG or acute PF in place of or incombination with cortisterods and optionally in combination with animmunosuppressive agent chosen from interferon alpha, interferon gamma,cyclophosphamide, tacrolimus, mycophenolate mofetil, methotrexate,dapsone, sulfasalazine, azathioprine, an anti-CD20 agent (such asrituximab, ofatumumab, obinutuzumab, or veltuzumab, or a biosimilarversion thereof), anti-TNFalpha agent (such as entanercept, infliximab,golilumab, adalimumab, or certolizumab pegol or a biosimilar versionthereof), anti-IL6 agent toward ligand or its receptors (such astocilizumab, sarilumab, olokizumab, elsililumab, or siltuximab),anti-IL17 agent to ligand or its receptors (such as secukinumab,ustekinumab, brodalumab, or ixekizumab), anti-IL1 agent to ligand or itsreceptors (such as with rilonacept, canakinumab, or anakinra), anti-IL2agent to ligand or its receptors (such as basiliximab or daclizumab),anti-CD2 agent such as alefacept, anti-CD3 agent such as muromonab-cd3,anti-CD80/86 agent such as abatacept or belatacept,anti-sphingosine-1-phosphate receptor agent such as fingolimod, anti-C5agent such as eculizumab, anti-integrin alpha4 agent such asnatalizumab, anti-α₄β₇ agent such as vedolizumab, anti-mTOR agent suchas sirolimus or everolimus, anti-calcineurin agent such as tacrolimus,or anti-BAFF/BlyS agent (such as belimumab, VAY736, or blisibimod),leflunomide and teriflunomide. Preferably, rituximab, ofatumumab,obinutuzumab, or veltuzumab, or a biosimilar version thereof.

In a sixth embodiment of the first, second, third, fourth, and fifthaspects, and the first second, and third embodiments contained therein,the BTK inhibitor is administered in acute pemphigus vulgaris or acutepemphigus foliaceus in place of corticosteroids and optionally incombinations with an immunosuppressive agent chosen from interferonalpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolatemofetil, methotrexate, dapsone, sulfasalazine, azathioprine, ananti-CD20 agent (such as rituximab, ofatumumab, obinutuzumab, orveltuzumab, or a biosimilar version thereof), anti-TNFalpha agent (suchas entanercept, infliximab, golilumab, adalimumab, or certolizumab pegolor a biosimilar version thereof), anti-IL6 agent toward ligand or itsreceptors (such as tocilizumab, sarilumab, olokizumab, elsililumab, orsiltuximab), anti-IL17 agent to ligand or its receptors (such assecukinumab, ustekinumab, brodalumab, or ixekizumab), anti-IL1 agent toligand or its receptors (such as with rilonacept, canakinumab, oranakinra), anti-IL2 agent to ligand or its receptors (such asbasiliximab or daclizumab), anti-CD2 agent such as alefacept, anti-CD3agent such as muromonab-cd3, anti-CD80/86 agent such as abatacept orbelatacept, anti-sphingosine-1-phosphate receptor agent such asfingolimod, anti-C5 agent such as eculizumab, anti-integrin alpha4 agentsuch as natalizumab, anti-α₄β₇ agent such as vedolizumab, anti-mTORagent such as sirolimus or everolimus, anti-calcineurin agent such astacrolimus, or anti-BAFF/BlyS agent (such as belimumab, VAY736, orblisibimod), leflunomide and teriflunomide. Preferably, rituximab,ofatumumab, obinutuzumab, or veltuzumab, or a biosimilar versionthereof. In yet another embodiment of any of the above aspects, the BTKinhibitor is injected locally into the patient to treat the condition ofsmall areas of the body. Examples of conditions for which localinjections can be used include inflammation of a bursa (bursitis of thehip, knee, elbow, or shoulder), a tendon (tendinitis, such as tenniselbow), and a joint (arthritis). Knee osteoarthritis, hip bursitis,painful foot conditions such as plantar fasciitis, and rotator cufftendinitis may be treated by local injection of a BTK inhibitor.

In a sixth aspect, provided is a method of treating an autoimmunedisease and/or inflammatory disease in a mammal which method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of a BTK inhibitor in combination with an immunosuppressive agenthaving slow manifestations of clinical effect. In one embodiment, theimmunosuppressive agent is a biologic chosen from as interferon alpha,interferon gamma, an anti-CD20 agent (such as rituximab, ofatumumab,obinutuzumab, veltuzumab, or a biosimilar version thereof),anti-TNFalpha agent (such as entanercept, infliximab, golilumab,adalimumab, certolizumab pegol or a biosimilar version thereof),anti-IL6 agent toward ligand or its receptors (such as tocilizumab,sarilumab, olokizumab, elsililumab, or siltuximab), anti-IL17 agent toligand or its receptors (such as secukinumab, ustekinumab, brodalumab,or ixekizumab), anti-IL1 agent to ligand or its receptors (such as withrilonacept, canakinumab, or anakinra), anti-IL2 agent to ligand or itsreceptors such as with basiliximab or daclizumab, anti-CD2 agent such asalefacept, anti-CD3 agent such as muromonab-cd3, anti-CD80/86 agent suchas with abatacept orbelatacept, anti-C5 agent such as eculizumab,anti-integrin alpha4 agent such as natalizumab, anti-α₄β₇ agent such asvedolizumab, and anti-BAFF/BlyS agent (such as belimumab, VAY736, orblisibimod). Preferably, rituximab, ofatumumab, obinutuzumab, orveltuzumab, or a biosimilar version thereof.

Representative advantages of the above methods, include sparing thepatient of disease activity without immunosuppression for prolongedperiods that can lead to serious side effects. Additionally, the longerthe acute flares and acute phases persist the more likely the diseaseprocess will progress and cause serious complications. Thus promptremission of acute phases and acute flares will have a beneficial effecton the course of the disease, even without continued administration ormaintenance of the active agents.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor is acompound of Formula (I):

wherein:

dashed lines are an optional bond;

Z¹, Z², and Z³ are —N— or —CH—, provided that one or two of Z¹, Z², andZ³ are simultaneously —N—;

L is O, NR, NRCO, CONR, or NR′CONR where each R and R′ is independentlyhydrogen or alkyl;

Ar is aryl, heteroaryl, cycloalkyl or heterocyclyl;

R² is hydrogen, alkyl, hydroxy, alkoxy, cyano, halo or haloalkyl;

R³ and R⁴ are independently hydrogen, alkyl, cyclopropyl, hydroxy,alkoxy, cyano, halo, haloalkyl or haloalkoxy;

R⁵, R⁶ and R⁷ are independently hydrogen, alkyl, hydroxy, alkoxy, halo,haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl, cyano, —CONH₂, amino,alkylamino, or dialkylamino;

Z is -alkyleneCO—, -alkyleneOCO—, -alkyleneSO₂—,

(where Z′ is bond or alkylene, and ring A is heterocycloamino optionallysubstituted with one or two substituents independently selected fromalkyl, hydroxy and fluoro, -(alkylene)-NR^(a)CO— or-(alkylene)-NR^(a)SO₂— (where each R^(a) is hydrogen, alkyl orcycloalkyl);

R^(b) is hydrogen, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylthio,or alkylsulfonyl;

R^(c) is hydrogen, alkyl, haloalkoxy, substituted alkyl, cycloalkyl,cycloalkyleneNR^(d)R^(e) (where R^(d) and R^(c) are independentlyhydrogen, alkyl, or cycloalkyl), or 3 to 6 membered saturated monocyclicheterocyclyl containing one or two heteroatoms selected from N, O, or Sand optionally substituted with one or two substituents independentlyselected from hydroxy, alkyl or fluoro;

-   -   and/or a pharmaceutically acceptable salt thereof;        wherein the terms are as defined below.

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, butyl (including all isomeric forms), pentyl (including allisomeric forms), and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms unless otherwise stated e.g., methylene,ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene,pentylene, and the like.

“Alkylthio” means an —SR radical where R is alkyl as defined above,e.g., methylthio, ethylthio, and the like.

“Alkylsulfonyl” means an —SO₂R radical where R is alkyl as definedabove, e.g., methylsulfonyl, ethylsulfonyl, and the like.

“Amino” means an —NH₂.

“Alkylamino” means an —NHR radical where R is alkyl as defined above,e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and thelike.

“Alkoxy” means an —OR radical where R is alkyl as defined above, e.g.,methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, andthe like.

“Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with an alkoxy group, or one or two alkoxygroups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or3-methoxypropyl, 2-ethoxyethyl, and the like.

“Alkoxycarbonyl” means a —C(O)OR radical where R is alkyl as definedabove, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 10 ring atoms e.g., phenyl or naphthyl.

“Cycloalkyl” means a cyclic saturated monovalent hydrocarbon radical ofthree to ten carbon atoms wherein one or two carbon atoms may bereplaced by an oxo group, e.g., cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, and the like.

“Cycloalkylene” means a cyclic saturated divalent hydrocarbon radical ofthree to ten carbon atoms wherein one or two carbon atoms may bereplaced by an oxo group, e.g., cyclopropylene, cyclobutylene,cyclopentylene, or cyclohexylene, and the like.

“Carboxy” means —COOH.

“Dialkylamino” means an —NRR′ radical where R and R′ are independentlyalkyl, as defined above.

“Halo” means fluoro, chloro, bromo, or iodo. In one embodiment halo isfluoro or chloro.

“Haloalkyl” means alkyl radical as defined above, which is substitutedwith a halogen atoms or one to five halogen atoms (in one embodimentfluorine or chlorine), including those substituted with differenthalogens, e.g., —CH₂Cl, —CF₃, —CHF₂, —CH₂CF₃, —CF₂CF₃, —CF(CH₃)₂, andthe like. When the alkyl is substituted with only fluoro, it is referredto in this Application as fluoroalkyl.

“Haloalkoxy” means a —OR radical where R is haloalkyl as defined abovee.g., —OCF₃, —OCHF₂, and the like. When R is haloalkyl where the alkylis substituted with only fluoro, it is referred to in this Applicationas fluoroalkoxy.

“Hydroxyalkyl” means an alkyl, as defined above, substituted with one ortwo hydroxy groups, provided that if two hydroxy groups are present theyare not both on the same carbon atom. Representative examples include,but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl,3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl,3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl,1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyland 2-(hydroxymethyl)-3-hydroxypropyl. In one embodiment,2-hydroxyethyl, 2,3-dihydroxypropyl, and1-(hydroxymethyl)-2-hydroxyethyl.

“Heterocyclyl” means a saturated or unsaturated monovalent monocyclicgroup of 4 to 8 ring atoms in which one or two ring atoms areheteroatoms selected from N, O, or S(O)_(n), where n is an integer from0 to 2, the remaining ring atoms being C. The heterocyclyl ring isoptionally fused to an (one) aryl or heteroaryl ring as defined hereinprovided the aryl and heteroaryl rings are monocyclic. The heterocyclylring fused to monocyclic aryl or heteroaryl ring is also referred to inthis Application as “bicyclic heterocyclyl” ring, even though a portionof the bicycle is aromatic. Additionally, one or two ring carbon atomsin the heterocyclyl ring can optionally be replaced by a —CO— group.More specifically the term heterocyclyl includes, but is not limited to,pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl,2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl,thiomorpholino, and the like. When the heterocyclyl ring is unsaturatedit can contain one or two ring double bonds provided that the ring isnot aromatic. When the heterocyclyl group contains a nitrogen atom, itis also referred to herein as heterocycloamino and is a subset of theheterocyclyl group. When the heterocyclyl group is a saturated ring andis not fused to aryl or heteroaryl ring as stated above, it is alsoreferred to herein as saturated monocyclic heterocyclyl.

“Heterocycloamino” means a saturated or unsaturated monovalentmonocyclic group of 4 to 8 ring atoms in which one or two ring atoms areheteroatom selected from N. O, or S(O)_(n), where n is an integer from 0to 2, the remaining ring atoms being C provided that a ring atom is N.Additionally, one or two ring carbon atoms in the heterocycloamino ringcan optionally be replaced by a —CO— group. When the heterocycloaminoring is unsaturated it can contain one or two ring double bonds providedthat the ring is not aromatic.

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radicalof 5 to 10 ring atoms where one or more, or one, two, or three, ringatoms are heteroatom selected from N, O, or S, the remaining ring atomsbeing carbon. Representative examples include, but are not limited to,pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl,oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl,isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazolyl, tetrazolyl, and the like.

“Oxo” or “carbonyl” means C═(O) group.

“Substituted alkyl” means alkyl group as defined herein which issubstituted with one, two, or three substituents independently selectedfrom hydroxyl, alkoxy, carboxy, cyano, carboxy, alkoxycarbonyl,alkylthio, alkylsulfonyl, halo, —CONRR′ or —NRR′ (where each R ishydrogen, alkyl, cycloalkyl, hydroxyalkyl, or alkoxyalkyl, and each R′is hydrogen, alkyl, or cycloalkyl), heterocyclyl (in one embodimentheterocycloamino as defined herein) which is optionally substituted withone or two groups independently selected from alkyl, hydroxyl, alkoxy,alkylthio, alkylsulfonyl, halo, or —CONRR′ where R and R′ are as definedabove,

where one or two of X¹, X² and X³ are nitrogen and the rest are carbonand the ring is optionally substituted with one or two substituentsindependently selected from alkyl, haloalkyl, or halo.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “heterocyclyl group optionallysubstituted with an alkyl group” means that the alkyl may but need notbe present, and the description includes situations where theheterocyclyl group is substituted with an alkyl group and situationswhere the heterocyclyl group is not substituted with alkyl.

In one embodiment, the compound of Formula (I) is:

-   2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   2-(2-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   2-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   2-(3-(4-amino-3-(4-(3,4-dichlorophenoxy)-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   2-(2-((4-amino-3-(4-(3,4-dichlorophenoxy(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   2-(4-(4-amino-3-(4-(3,4-dichlorophenoxy)-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile,-   2-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   2-(4-(4-amino-3-(4-(3,4-dichlorophenoxy)-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   2-(2-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-2-cyano-3-cyclopropylacrylamide;-   2-(2-((4-amino-3-(4-(3,4-dichlorophenoxy)-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   N-((1r,4r)-4-(4-amino-3-(4-(3,4-dichlorophenoxy)-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-2-cyano-3-cyclopropylacrylamide;-   N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-2-cyano-4,4-dimethylpent-2-enamide;-   (R)-2-(3-(4-amino-3-(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   N-((1r,4r)-4-(4-amino-3-(4-(3,4-dichlorophenoxy)-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-2-cyano-4,4-dimethylpent-2-enamide;-   (R)-2-(3-(4-amino-3-(4-(3,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(3,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-(phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-(phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   2-(3-(4-amino-3-(4-(3,4-dichlorophenoxy)-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   N-((1s,4s)-4-(4-amino-3-(4-(3,4-dichlorophenoxy)-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-2-cyano-3-cyclopropylacrylamide;-   N-((1s,4s)-4-(4-amino-3-(4-(3,4-dichlorophenoxy)-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-2-cyano-4,4-dimethylpent-2-enamide;-   (R)-2-(2-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile-   (S)-2-(2-((4-amino-3-(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(3,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-3-(4-(3,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   2-(3-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[34-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(3-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-cyano-3-cyclopropylacrylamide;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(3-(4-amino-3-(4-(2,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(2,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(2,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-3-(4-(2,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-(3,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-(3,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(3-fluoro-4-(phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-3-(3-fluoro-4-(phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   N-(2-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-cyano-3-cyclopropylacrylamide;-   N-(2-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylpropyl)-2-cyano-3-cyclopropylacrylamide;-   N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylpropan-2-yl)-2-cyano-3-cyclopropylacrylamide;-   N-(2-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-cyano-2-cyclopropylethenesulfonamide;-   N-(2-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-cyano-2-cyclopropyl-N-methylethenesulfonamide;-   2-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl    2-cyano-3-cyclopropylacrylate;-   1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylpropan-2-yl    2-cyano-3-cyclopropylacrylate;-   2-((2-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)sulfonyl)-3-cyclopropylacrylonitrile,-   2-(5-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)oxazol-2-yl)-3-cyclopropylacrylonitrile;-   (R)-2-(3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(3-(4-amino-5-(4-(3,5-difluorophenoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(3-(4-amino-5-(4-(3,5-difluorophenoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(3-(4-amino-5-(2-fluoro-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(3-(4-amino-5-(2-fluoro-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-5-(4-(3,5-difluorophenoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-5-(4-(3,5-difluorophenoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-5-(2-fluoro-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-5-(2-fluoro-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(3-(4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(3-(4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(3-(4-amino-5-(4-(3,5-difluorophenoxy)phenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(3-(4-amino-5-(4-(3,5-difluorophenoxy)phenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   2-((3R)-3-(4-amino-5-(2-fluoro-4-phenoxyphenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   2-((3S)-3-(4-amino-5-(2-fluoro-4-phenoxyphenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-(2-(2-((4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-(2-(2-((4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-5-(4-(3,5-difluorophenoxy)phenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-5-(4-(3,5-difluorophenoxy)phenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-5-(2-fluoro-4-phenoxyphenyl)-6-methy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-5-(2-fluoro-4-phenoxyphenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   2-(3-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethylpropyl)-2-cyano-3-cyclopropylacrylamide;-   2-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridin-2-yl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(2-methyl-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-3-(2-methyl-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(2-chloro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-3-(2-chloro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(2,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-(2,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-4-amino-2-(2-((4-amino-3-(2-fluoro-4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-4-amino-2-(2-((4-amino-3-(2-fluoro-4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(4-(2,6-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-(2,6-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4,4-difluoropyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4,4-difluoropyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4,4-difluoropyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4,4-difluoropyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-4-amino-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-4-amino-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(methylamino)pent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(methylamino)pent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(ethylamino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(ethylamino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(isopropylamino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(isopropylamino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(cyclopropylamino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(cyclopropylamino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-((2-methoxyethyl)amino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-((2-methoxyethyl)amino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-ethoxy-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-ethoxy-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-aminocyclopropyl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-aminocyclopropyl)acrylonitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-(methylamino)cyclopropyl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-(methylamino)cyclopropyl)acrylonitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-(ethylamino)cyclopropyl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-(ethylamino)cyclopropyl)acrylonitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-(isopropylamino)cyclopropyl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-(isopropylamino)cyclopropyl)acrylonitrile;-   2-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(pyrrolidin-2-yl)acrylonitrile;-   2-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(pyrrolidin-2-yl)acrylonitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-((dimethylamino)methyl)cyclopentyl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-((dimethylamino)methyl)cyclopentyl)acrylonitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-methylpiperidin-4-yl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-methylpiperidin-4-yl)acrylonitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)acrylonitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(piperidin-4-yl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(piperidin-4-yl)acrylonitrile;-   2-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-1)methyl)pyrrolidine-1-carbonyl)-3-(piperidin-3-yl)acrylonitrile;-   2-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(piperidin-3-yl)acrylonitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (S)-4-amino-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-4-amino-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(methylamino)pent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(methylamino)pent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(ethylamino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(ethylamino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(isopropylamino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(isopropylamino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(cyclopropylamino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(cyclopropylamino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-((2-methoxyethyl)amino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-((2-methoxyethyl)amino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-ethoxy-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-ethoxy-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-aminocyclopropyl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-aminocyclopropyl)acylonitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-(methylamino)cyclopropyl)-acrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-(methylamino)cyclopropyl)-acrylonitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-(ethylamino)cyclopropyl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-(ethylamino)cyclopropyl)acylonitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-(isopropylamino)cyclopropyl)-acrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-(isopropylamino)cyclopropyl)-acrylonitrile;-   2-((S)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(pyrrolidin-2-yl)acrylonitrile;-   2-((R)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(pyrrolidin-2-yl)acrylonitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-((diethylamino)methyl)cyclopentyl)-acrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-((diethylamino)methyl)cyclopentyl)-acrylonitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-((dimethylamino)methyl)-cyclopentyl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-((dimethylamino)-methyl)-cyclopentyl)acrylonitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-methylpiperidin-4-yl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-methylpiperidin-4-yl)acrylonitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)acrylonitrile;-   (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(piperidin-4-yl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(piperidin-4-yl)acrylonitrile;-   2-((S)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(piperidin-3-yl)acrylonitrile;-   2-((R)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(piperidin-3-yl)acrylonitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolol[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (R)-4-amino-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-4-amino-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(methylamino)pent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(methylamino)pent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolol[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(ethylamino)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(ethylamino)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(isopropylamino)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(isopropylamino)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(cyclopropylamino)-4-methylpent-2-enenitrile-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(cyclopropylamino)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolol[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((2-methoxyethyl)amino)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((2-methoxyethyl)amino)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-ethoxy-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-ethoxy-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolol[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-aminocyclopropyl)acrylonitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-aminocyclopropyl)acrylonitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-(methylamino)cyclopropyl)acrylonitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-(methylamino)cyclopropyl)acrylonitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-(ethylamino)cyclopropyl)acrylonitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-(ethylamino)cyclopropyl)acrylonitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolol[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-(isopropylamino)cyclopropyl)acrylonitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-(isopropylamino)cyclopropyl)acrylonitrile;-   2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(pyrrolidin-2-yl)acrylonitrile,-   2-((S)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(pyrrolidin-2-yl)acrylonitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolol[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-((diethylamino)methyl)-cyclopentyl)acrylonitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-((diethylamino)methyl)-cyclopentyl)acrylonitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-((dimethylamino)methyl)cyclopentyl)-acrylonitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-((dimethylamino)methyl)cyclopentyl)-acrylonitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-methylpiperidin-4-yl)acrylonitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-methylpiperidin-4-yl)acrylonitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)acrylonitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)acrylonitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(piperidin-4-yl)acylonitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(piperidin-4-yl)acrylonitrile;-   2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(piperidin-3-yl)acrylonitrile;-   2-((S)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(piperidin-3-yl)acylonitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile,-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (R)-4-amino-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-4-amino-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(methylamino)pent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(methylamino)pent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(ethylamino)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(ethylamino)-4-methylpent-2-enenitrile,-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(isopropylamino)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(isopropylamino)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(cyclopropylamino)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(cyclopropylamino)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((2-methoxyethyl)amino)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((2-methoxyethyl)amino)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-ethoxy-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-ethoxy-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-aminocyclopropyl)-acrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-aminocyclopropyl)-acrylonitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-(methylamino)cyclopropyl)-acrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-(methylamino)cyclopropyl)-acrylonitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-(ethylamino)cyclopropyl)-acrylonitrile-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-(ethylamino)cyclopropyl)-acrylonitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-(isopropylamino)-cyclopropyl)acrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-(isopropylamino)-cyclopropyl)acrylonitrile;-   2-((R)-3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(pyrrolidin-2-yl)acrylonitrile;-   2-((S)-3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(pyrrolidin-2-yl)acrylonitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-((diethylamino)methyl)-cyclopentyl)-acrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-((diethylamino)methyl)-cyclopentyl)-acrylonitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-((dimethylamino)-methyl)cyclopentyl)-acrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-((dimethylamino)-methyl)cyclopentyl)-acrylonitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-methylpiperidin-4-yl)acrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(1-methylpiperidin-4-yl)acrylonitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)acrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)acrylonitrile;-   (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(piperidin-4-yl)acrylonitrile;-   (S)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(piperidin-4-yl)acrylonitrile;-   2-((R)-3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(piperidin-3-yl)acrylonitrile;-   2-((S)-3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-(piperidin-3-yl)acrylonitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(piperidin-1-yl)pent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(piperidin-1-yl)pent-2-enenitrile;-   (R)-2-(2-((4-amino-5-(2-fluoro-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-5-(2-fluoro-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-5-(4-(2,3-difluorophenoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (S)-2-(2-((4-amino-5-(4-(2,3-difluorophenoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;-   (R)-2-(2-((4-amino-5-(4-(2,3-difluorophenoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-5-(4-(2,3-difluorophenoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-5-(4-(2,3-difluorophenoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (S)-2-(2-((4-amino-5-(4-(2,3-difluorophenoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;-   (R)-2-(2-((4-amino-5-(4-(2,3-difluorophenoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-5-(4-(2,3-difluorophenoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-4-amino-2-(2-((4-amino-5-(2-fluoro-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-4-amino-2-(2-((4-amino-5-(2-fluoro-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-methyl)pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-methyl)pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-methyl)pyrrolidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile-   (S)-2-(2-((4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-methyl)pyrrolidine-1-carbonyl)-4-methyl-4-morpholinopent-2-enenitrile;-   (R)-2-(2-((4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-   methyl)pyrrolidine-1-carbonyl)-4-(diethylamino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-methyl)pyrrolidine-1-carbonyl)-4-(diethylamino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-methyl)pyrrolidine-1-carbonyl)-4-ethoxy-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-methyl)pyrrolidine-1-carbonyl)-4-ethoxy-4-methylpent-2-enenitrile;-   (R)—N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-propan-2-yl)-2-cyano-4,4-dimethylpent-2-enamide;-   (S)—N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-yl)-2-cyano-4,4-dimethylpent-2-enamide;-   (R)—N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-yl)-2-cyano-4-methylpent-2-enamide;-   (S)—N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-yl)-2-cyano-4-methylpent-2-enamide;-   (R)—N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-yl)-2-cyano-4-ethoxy-4-methylpent-2-enamide;-   (S)—N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-yl)-2-cyano-4-ethoxy-4-methylpent-2-enamide;-   (R)—N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-yl)-2-cyano-4-(dimethylamino)-4-methylpent-2-enamide;-   (S)—N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-yl)-2-cyano-4-(dimethylamino)-4-methylpent-2-enamide;-   2-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-((S)-pyrrolidin-2-yl)acrylonitrile;-   2-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-((R)-pyrrolidin-2-yl)acrylonitrile;-   (R)-4-amino-N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)propan-2-yl)-2-cyano-4-methylpent-2-enamide;-   (S)-4-amino-N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)propan-2-yl)-2-cyano-4-methylpent-2-enamide;-   N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-cyano-3-cyclopropyl-N-methylacrylamide;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(piperidin-1-yl)pent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(piperidin-1-yl)pent-2-enenitrile;-   (S)—N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-yl)-2-cyano-4,4-dimethylpent-2-enamide;-   (S)—N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-yl)-2-cyano-4-methylpent-2-enamide;-   (S)—N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-yl)-2-cyano-4-(dimethylamino)-4-methylpent-2-enamide;-   (S)—N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-yl)-2-cyano-4-ethoxy-4-methylpent-2-enamide;-   (S)-4-amino-N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)propan-2-yl)-2-cyano-4-methylpent-2-enamide;-   (S)—N-(1-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-yl)-2-cyano-3-cyclopropylacrylamide;-   2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile;-   2-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile;-   2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-piperazin-1-yl-pent-2-enenitrile;-   2-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-piperazin-1-yl-pent-2-enenitrile;-   2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-[methyl(oxetan-3-yl)amino]pent-2-enenitrile;-   2-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-[methyl(oxetan-3-yl)amino]pent-2-enenitrile;-   2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(oxetan-3-ylamino)pent-2-enenitrile;-   2-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(oxetan-3-ylamino)pent-2-enenitrile;-   2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[methyl(oxetan-3-yl)amino]pent-2-enenitrile;-   2-[(3S)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[methyl(oxetan-3-yl)amino]pent-2-enenitrile;-   2-[[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl]-piperidin-1-yl]carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile;-   2-[[(3S)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl]-piperidin-1-yl]carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile;-   2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(piperazin-1-yl)pent-2-enenitrile;-   2-((S)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(piperazin-1-yl)pent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(ethyl(oxetan-3-yl)amino)-4-methylpent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(ethyl(oxetan-3-yl)amino)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(ethyl(oxetan-3-yl)amino)pent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(ethyl(oxetan-3-yl)amino)pent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolol[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pent-2-enenitrile;-   2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(4-ethylpiperazin-1-yl)pent-2-enenitrile;-   2-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(4-ethylpiperazin-1-yl)pent-2-enenitrile;-   2-[[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl]-piperidin-1-yl]carbonyl]-4-methyl-4-(4-ethylpiperazin-1-yl)pent-2-enenitrile;-   2-[[(3S)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl]-piperidin-1-yl]carbonyl]-4-methyl-4-(4-ethylpiperazin-1-yl)pent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(oxetan-3-yl)aminopent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(oxetan-3-yl)aminopent-2-enenitrile;-   (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(cyclopropyl(oxetan-3-yl)amino)-4-methylpent-2-enenitrile;-   (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(cyclopropyl(oxetan-3-yl)amino)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[34-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(cyclopropyl(oxetan-3-yl)amino)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(cyclopropyl(oxetan-3-yl)amino)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-isopropylpiperazin-1-yl)-4-methylpent-2-enenitrile,-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-isopropylpiperazin-1-yl)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-(tert-butyl)piperazin-1-yl)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-(tert-butyl)piperazin-1-yl)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)-4-methylpent-2-enenitrile;-   2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((R)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpent-2-enenitrile;-   2-((S)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((R)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpent-2-enenitrile;-   2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpent-2-enenitrile;-   2-((S)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pent-2-enenitrile;-   2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pent-2-enenitrile;-   2-((S)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pent-2-enenitrile;-   2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((3S,5R)-3,5-dimethylpiperazin-1-vi)-4-methylpent-2-enenitrile;-   2-((S)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-4-methylpent-2-enenitrile;-   2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((2R,5S)-2,5-dimethylpiperazin-1-yl)-4-methylpent-2-enenitrile;-   2-((S)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((2R,5S)-2,5-dimethylpiperazin-1-vi)-4-methylpent-2-enenitrile;-   2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-((2R,5S)-2,4,5-trimethylpiperazin-1-yl)pent-2-enenitrile;-   2-((S)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-((2R,5S)-2,4,5-trimethylpiperazin-1-yl)pent-2-enenitrile;-   2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methylpent-2-enenitrile;-   2-((S)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methylpent-2-enenitrile;-   2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-((2S,5R)-2,4,5-trimethylpiperazin-1-yl)pent-2-enenitrile;-   2-((S)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-((2S,5R)-2,4,5-trimethylpiperazin-1-yl)pent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-4-methylpent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-4-methylpent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(methylsulfonyl)piperazin-1-yl)pent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(methylsulfonyl)piperazin-1-yl)pent-2-enenitrile;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-methyl-3-oxopiperazin-1-yl)pent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-methyl-3-oxopiperazin-1-yl)pent-2-enenitrile;-   (R)-4-(4-acetylpiperazin-1-yl)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (S)-4-(4-acetylpiperazin-1-yl)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile;-   (R)-methyl    4-(5-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)piperazine-1-carboxylate;-   (S)-methyl    4-(5-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)piperazine-1-carboxylate;-   (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethyl-5-morpholinopent-2-enenitrile;-   (S)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethyl-5-morpholinopent-2-enenitrile;

or a mixture of R and S isomers thereof;

or an individual E or Z isomer of any of the above compounds; and/or

a pharmaceutically acceptable salt of any of the above compounds.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor is acompound of formula (Ia) or (Ib) disclosed on pages 4-6, and specificcompounds disclosed on pages 57-94, of PCT application publication no.WO 2009/158571, the disclosure of those pages relating to the BTKinhibitor is incorporated herein by reference in their entirety. Thescope of the terms in compound for formula (Ia) and (Ib) are disclosedon pages 4-6 are as defined on pages 6-14 of WO 2009/158571, thedisclosure of those pages relating to definitions is incorporated hereinby reference in their entirety. In one embodiment, the compound isN-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)-pyrimidin-4-yl)amino)phenyl)acrylamideand/or a pharmaceutically acceptable salt thereof.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitors arecompounds of formula (I) disclosed on pages 1 and 2, paragraph [0005]and the specific compound disclosed on page 3, paragraph [0008] of PCTapplication publication no. WO 2013/173518, the disclosure of thosepages relating to the BTK inhibitor is incorporated herein by referencein their entirety. The scope of the terms in formula (I) is disclosed onpages 1 and 2 as defined on pages 4-7, paragraphs [0013]-[0031] of WO2013/173518 and the disclosure of those pages relating to scope of theterms is incorporated herein by reference in their entirety.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitors arecompounds of formula (I) disclosed on pages 2 and 3, paragraph [0007],formula (Ia), paragraph [0014] disclosed on pages 5 and 6, formula (Ib),paragraph [0021] disclosed on pages 7-9, formula (II) on pages 12-13,paragraph [0043], formula (III) on pages 65-66, paragraph [00250], andformula (IV) disclosed on pages 75-76, paragraph [00272], and thespecific compound disclosed on pages 80-85 and pages 165-175 of PCTapplication publication no. WO 2013/102059, the disclosure of thosepages relating to BTK inhibitors is incorporated herein by reference intheir entirety. The scope of the terms used to define the compounds offormulae (I), (Ia), (II), (III) and (IV) are as defined on pages 26-35,paragraphs [00104]-[00163], [00167], [00177] of WO 2013/102059 and thedisclosure of those pages relating to scope is incorporated herein byreference in their entirety.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitors arecompounds of formula (I) disclosed on pages 2 and 3, paragraph [0007],formula (Ia) disclosed on pages 46-48, paragraph [00207], formula (Ib)disclosed on pages 51-53, paragraph [00218], formula (III) on pages 4-5,paragraph [0009], formula (II) on pages 57 and 58, paragraph [00229],and formula (IV) disclosed on pages 63-65, paragraph [00249], and thespecific compound disclosed on pages 66-75 of PCT applicationpublication no. WO 2014/078578, the disclosure of those pages relatingto BTK inhibitors is incorporated herein by reference in their entirety.The scope of the terms used to define the compounds of formulae (I),(Ia), (II), (III) and (IV) are as defined on pages 18-28, paragraphs[0066]-[00133], [00137], [00147] of WO 2014/078578 and the disclosure ofthose pages relating to scope is incorporated herein by reference intheir entirety.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor is acompound of formula (I) disclosed on pages 2 and 3, paragraph [0007],formula (II) disclosed on pages 6 and 7, paragraph [0014], formula (III)on pages 8-10, paragraph [0019], formula (Ia) disclosed on pages 50-52,paragraph [00219], formula (Ib) disclosed on pages 54-56, paragraph[00228], formula (II), page 58-60, paragraph [00237], formula (IIa)disclosed on pages 63-65, paragraph [00247], formula (IIb) disclosed onpages 67-69, paragraph [00255], formula (III), page 71-73, paragraph[00263], formula (IIIa) disclosed on pages 77-79, paragraph [00277],formula (IIIb) disclosed on pages 82-83, paragraph [00286], formula(IIIc) disclosed on pages 86-87, paragraph [00295], and the specificcompound disclosed on pages 91-102 of PCT application publication no. WO2013/116382, the disclosure of those pages relating to BTK inhibitor isincorporated herein by reference in their entirety. The scope of theterms used to define the compounds of formulae (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb) and (IIIc) are as defined on pages25-36, paragraphs [0088]-[00155], [00164], of WO 2013/116382 and thedisclosure of those pages relating to scope is incorporated herein byreference in their entirety.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor is acompound of formula (A) disclosed on pages 25 and 26, paragraph [00185],formula (B) disclosed on pages 26 and 27, paragraph [00186], formula (C)on pages 27-28, paragraph [00189], formula (D) disclosed on page 28-29,paragraph [00196], and the specific compound disclosed on pages 30-31,of PCT application publication no. WO 2008/039218, the disclosure ofthose pages relating to BTK inhibitor is incorporated herein byreference in their entirety. The scope of the terms in compounds offormulae (A), (B), (C), and (D) are as defined on pages 11-17 of WO2008/039218, paragraph [0061]-[00119], [00123], [00133], and thedisclosure of those pages relating to scope is incorporated herein byreference in their entirety. In one embodiment, the compound is BTKinhibitor Ibrutinib.

In another embodiment of the first, second, and third aspects andembodiments contained therein, the BTK inhibitor is a compound offormula (I) disclosed on pages 2 and 3, paragraph [0007], formula (II),pages 4-7, paragraph [0013], formula (Ia), paragraph [00216], formula(Ib), paragraph [00227], formula (Ic), paragraph [00237], formula (Id),paragraph [00247], formula (IIa), paragraph [00271], formula (III),paragraph [00283], formula (IIIa), paragraph [00293], formula (IV),paragraph [00304], formula (IVa), paragraph [00315], and the specificcompounds no. 6, 13, 17, 23, 29, 35, 43, 48, 54 and 60 of PCTapplication publication no. WO 2014/130693 the disclosure of those pagesrelating to BTK inhibitor is incorporated herein by reference in theirentirety. The scope of the terms in compounds of formula (I) are definedon pages 22-32, paragraph [0079]-[00146], [00160], of WO 2014/130693 andthe disclosure of those pages relating to scope is incorporated hereinby reference in their entirety.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor is acompound of formula (I) disclosed on pages 22-24, lines 21-11 andspecific compounds disclosed in table 1 page 28-34 of PCT applicationpublication no. WO 2013/067277, the disclosure of those pages relatingto BTK inhibitor is incorporated herein by reference in their entirety.The scope of the terms used to define the compounds of formula (I) areas defined on pages 6-11, lines 25 to 28 of WO 2013/067277 and thedisclosure of those pages relating to scope is incorporated herein byreference in their entirety.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor is acompound of formula (I) disclosed on pages 24-26, lines 1 to 15, andspecific compounds disclosed in table 1 page 34-78 of PCT applicationpublication no. WO 2013/067274, the disclosure of those pages relatingto BTK inhibitor is incorporated herein by reference in their entirety.The scope of the terms used to define the compounds of formula (I) areas defined on pages 8-13, lines 1 to 5 of WO 2013/067274 are thedisclosure of those pages relating to scope is incorporated herein byreference in their entirety.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor is acompound of formula (I) disclosed on pages 19-20, lines 1 to 5 andspecific compounds disclosed in table 1 page 32-94 of PCT applicationpublication no. WO 2011/140488, the disclosure of those pages relatingto BTK inhibitor is incorporated herein by reference in their entirety.The scope of the terms used to define the compounds of formula (I) areas defined on pages 4-8, lines 30 to 25 of WO 2011/140488 and thedisclosure of those pages relating to scope is incorporated herein byreference in their entirety.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor is acompound of formula (I) disclosed on page 3, paragraph [0022] andspecific compounds disclosed in table 1 pages 34-78 of US applicationpublication no. US 2013/0217880 and specific compounds disclosed thereinthe disclosure of those pages relating to BTK inhibitor is incorporatedherein by reference in their entirety. The scope of the terms used todefine the compounds of formula (I) are as defined on pages 4-5 of US2013/0217880 are the disclosure of those pages relating to scope isincorporated herein by reference in their entirety. In one embodimentthe compound is6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenylphenyl)-7,9-dihydro-8H-purin-8-oneand/or a salt thereof.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor is acompound of formula (I) disclosed on pages 4-14, lines 1 to 11 andspecific compounds disclosed in table 1 page 33-77 of PCT applicationpublication no. WO 2013/010380 and specific compounds disclosed thereinthe disclosure of those pages relating to BTK inhibitor is incorporatedherein by reference in their entirety. The scope of the terms used todefine the compounds of formula (I) are as defined on pages 14-23, lines13 to 4 of WO 2013/010380 and the disclosure of those pages relating toscope is incorporated herein by reference in their entirety.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor is acompound of formula (I) disclosed on pages 3-4, lines 4-28 and specificcompounds disclosed in table 1 page 10-16 of PCT application publicationno. WO 2013/010868 and specific compounds disclosed therein thedisclosure of those pages relating to BTK inhibitor is incorporatedherein by reference in their entirety. The scope of the terms used todefine the compounds of formula (I) are as defined on pages 4-6, lines30-37 of WO 2013/010868 and the disclosure of those pages relating toscope is incorporated herein by reference in their entirety.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor is acompound of formula (I) disclosed on pages 3-4, lines 5 to 31 andspecific compounds disclosed in table 1 page 43-47 of PCT applicationpublication no. WO 2013/010869 and specific compounds disclosed thereinthe disclosure of those pages relating to BTK inhibitor is incorporatedherein by reference in their entirety. The scope of the terms used todefine the compounds of formula (I) are as defined on pages 4-7, lines34 to 37 of WO 2013/010869 and the disclosure of those pages relating toscope is incorporated herein by reference in their entirety.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitors arethose disclosed in WO2014/025976, WO2014/151620, and WO2014/152114, thedisclosures of which related to BTK inhibitors are incorporated hereinby reference in their entirety.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor is(R,E)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrileor an (E), or (Z) isomer thereof, Ibrutinib (Pharmacyclics/Johnson andJohnson) AVL 263 and 293 (Avila Therapeutics, Celgene Corporation),GDC-0834 (Genentech), GDC0853 (Genentech), BMS-488516 and 509744(Bristol Myers Squibb), CGI-1746 (Gilead Sciences), CTA-056 (Genentech),HY-11066 (also CTK417891), ONO-4059 (Ono Pharmaceutical Co. Ltd),ONO-WG37 (Ono Pharmaceutical Co. Ltd), PLS-123 (Peking Univ.), RN486(Hoffmann Las Roche), HM71224 (Hanmi Pharmaceutical Co. Ltd.), orACP-196 (Acerta Pharma BV).

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor isABT-105 or ABBV-105 (AbbVie), AC0025 (ACEA Biosciences), BGB311(BeiGene), CC-292 (Celgene), EBI-1266 (Eternity Bioscience), MSC-2364447(Merck Biopharma), PF-06250112 and PF-303 (Pfizer), RG7625 and RG7880(Hoffmann La Roche), SNS-062 (Sunesis), TP-4207 (ToleroPharmaceuticals), or X-022 (X-Chem).

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor is

-   (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one,-   (R)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide,-   (S)-7-(1-acryloylpiperidine-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide.-   (S)-7-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide,-   N-(3-((2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide,-   1-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)oxy)phenyl)prop-2-en-1-one.-   (R)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one,-   N-(2-((6-((5-(5-fluoro-2-(hydroxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyridin-2-yl)amino)ethyl)acrylamide,-   N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide,-   (S)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-(2,4-difluorophenoxy)phenyl)-1H-pyrazole-4-carboxamide,-   6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide, or-   (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-N-(5-chlorobenzo[d]oxazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide.

In another embodiment of the first, second, third, fourth, fifth, orsixth aspects and embodiments contained therein, the BTK inhibitor ischosen from:

Other terms used herein have the following meaning unless statedotherwise:

“Acute” as used herein means a disease with a rapid onset and/or a shortcourse.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as formic acid, acetic acid,propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid salicylicacid, stearic acid, muconic acid, and the like; or

salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. It is understood that thepharmaceutically acceptable salts are non-toxic. Additional informationon suitable pharmaceutically acceptable salts can be found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, portions of which relate to suitable pharmaceuticallyacceptable salts are incorporated herein by reference. See also Berge atal., Pharmaceutical Salts, Journal of Pharmaceutical Sciences, 1, Volume66, Number 1, January 1997.

Treatment decisions often follow formal or informal algorithmicguidelines. Treatment options can often be ranked or prioritized intolines of therapy: first-line therapy, second-line therapy, third-linetherapy, and so on. First-line therapy is the first therapy that will betried. Its priority over other options is usually either (1) formallyrecommended on the basis of clinical trial evidence for itsbest-available combination of efficacy, safety, and tolerability or (2)chosen based on the clinical experience of the physician. If afirst-line therapy either fails to resolve the issue or producesintolerable side effects, additional (second-line) therapies may besubstituted or added to the treatment regimen, followed by third-linetherapies, and so on. Accordingly. “first-line” therapy as used hereinmeans therapy usually given when someone is diagnosed with a particulardisease or condition and can be categorized as standard of care.

“Maintenance therapy” as used herein means a therapy, therapeuticregimen, or course of therapy which is administered subsequent to aninitial course of therapy administered to a patient with a disease.Maintenance therapy can be used to halt, slow down, or even reverse theprogression of the disease, to maintain the improvement in healthachieved by the initial treatment and/or enhance the gains achieved bythe initial therapy.

“Flares” as used herein means an exacerbation of a chronic disease.Sometimes referred to as a flare-up, a flare occurs when symptoms of adisease that has been present for a time suddenly worsen. For example,in many arthritis conditions the joints can flare with worsening ofstiffness, pain, and swelling.

The compounds of the present disclosure may have stereocenter, i.e.,assymetric centers, also referenced as chiral centers. Compounds of thepresent disclosure containing an asymmetrically substituted atom may beisolated in optically active or racemic forms. It is well known in theart how to prepare optically active forms, such as by resolution ofmaterials. All chiral, diastereomeric, and racemic forms are within thescope of this disclosure, unless the specific stereochemistry orisomeric form is specifically indicated.

The compounds of the present disclosure can exist as tautomers and/orgeometric isomers. All possible tautomers and cis and trans isomers, asindividual forms and mixtures thereof are within the scope of thisdisclosure. Additionally, as used herein the term alkyl includes all thepossible isomeric forms of said alkyl group albeit only a few examplesare set forth. Furthermore, when the cyclic groups such as aryl,heteroaryl, heterocyclyl are substituted, the) include all thepositional isomers albeit only a few examples are set forth.Furthermore, all polymorphic forms and hydrates of a compound of Formula(I) (or any of the embodiments thereof described herein), are within thescope of this disclosure and claims appended hereto.

It will be understood by a person of ordinary skill in the art that whena compound is denoted as (R), it may contain the corresponding (S)stereoisomer as an impurity i.e., the (S) stereoisomer in less thanabout 1% by wt and vice versa. Accordingly, when the compound herein isdenotes as a mixture of (R) and (S) stereoisomers, it means that theamount of (R) or (S) enantiomer in the mixture is greater than about 1%by wt. Similar analysis applies with when a compound is denoted as the(E) isomer, (Z) isomer or a mixture of (E) and (Z) isomers. And herein,where the term ‘about’ is used with a numerical value, the numericalvalue may vary by ±10%.” Therefore, “about 1” denotes a range from 0.9to 1.1.

A “pharmaceutically acceptable carrier or excipient” means a carrier oran excipient that is useful in preparing a pharmaceutical compositionthat is generally safe, non-toxic and neither biologically nor otherwiseundesirable, and includes a carrier or an excipient that is acceptablefor veterinary use as well as human pharmaceutical use. And in thespecification, including the documents incorporated herein by reference,and in the claims, unless the context clearly dictates otherwise, theterm “a” has its customary meaning of “one or more.” Hence, “apharmaceutically acceptable carrier/excipient,” as used in thespecification and claims means one or more pharmaceutically acceptablecarrier/excipient.

“Treating,” “treat,” or “treatment” of a disease includes:

(1) inhibiting the disease, i.e., arresting or reducing the developmentof the disease or its clinical symptoms; or

(2) relieving the disease, i.e., causing regression of the disease orits clinical symptoms. A “therapeutically effective amount” means theamount of a compound of the present disclosure that, when administeredto a mammal, such as a human, for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” will vary depending on the compound, the disease and itsseverity and the age, weight, etc., of the mammal to be treated.

“Mammal” as used herein means animals such as dogs, cats, and humans,preferably humans.

Formulations and Administration

In general, the compounds of this disclosure will be administered in atherapeutically effective amount by any of the accepted modes ofadministration, such as oral, for agents that serve similar utilities.Therapeutically effective amounts of compounds this disclosure may rangefrom about 0.01 to about 500 mg per kg patient body weight per day,which can be administered in single or multiple doses. A suitable dosagelevel may be from about 0.1 to about 250 mg/kg per day, such as about0.5 to about 100 mg/kg per day.

A suitable dosage level may also be about 0.01 to about 250 mg/kg perday, such as about 0.05 to about 100 mg/kg per day, and further such asabout 0.1 to about 50 mg/kg per day. Within this range the dosage can beabout 0.05 to about 0.5, such as about 0.5 to about 5, and further suchas about 5 to about 50 mg/kg per day. For oral administration, thecompositions can be provided in the form of tablets containing about 1to about 1000 milligrams of the active ingredient, particularly about 1,5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750,800, 900, and 1000 milligrams of the active ingredient. The actualamount to be administered of the compound of this disclosure, i.e., theactive ingredient, will depend upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe patient, the potency of the compound being utilized, the route andform of administration, and other factors.

In general, compounds of this disclosure will be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal or by suppository), orparenteral (e.g., intramuscular, intravenous or subcutaneous)administration. The preferred manner of administration is oral using aconvenient daily dosage regimen, which can be adjusted according to thedegree of affliction. Compositions can take the form of tablets, pills,capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules, including enteric coated or delayedrelease tablets, pills or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area i.e., decreasing particle size.For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a cross-linked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability. The disclosures of those two patents are incorporatedby reference with respect to those portions relating to pharmaceuticalformulations.

The compositions comprise, in general, a compound of this disclosure) incombination with a pharmaceutically acceptable excipient.Pharmaceutically acceptable excipients are non-toxic, aidadministration, and do not adversely affect the therapeutic benefit ofthe compound of this disclosure. Such excipient may be any solid,liquid, semi-solid or, in the case of an aerosol composition, gaseousexcipient that is generally available to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this disclosurein aerosol form. Inert gases suitable for this purpose are nitrogen,carbon dioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences, edited by E. W. Martin(Mack Publishing Company, 20th ed., 2000), incorporated by referenceherein with respect to the portions relating to pharmaceuticalexcipients and their formulations.

The level of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt. %) basis, from about 0.01-99.99wt. % of a compound of this disclosure based on the total formulation,with the balance being a suitable pharmaceutical excipients. Forexample, the compound is present at a level of about 1-80 wt. %. Withrespect to the numerical range 0.01-99.99 “about” denotes less than0.01%. With respect to the numerical range 1 to 80, “about” denotes 0.05with respect to 1 and 10 with respect to 80, thus covering a range from0.05 to 90 wt. %.

The compounds of this disclosure may be used in combination with one ormore other drugs in the treatment of diseases or conditions for whichcompounds of this disclosure or the other drugs may have utility. Suchother drug(s) may be administered, by a route and in an amount commonlyused therefore, contemporaneously, such as fixed dose combination, orsequentially with a compound of the present disclosure. When a compoundof this disclosure is used contemporaneously with one or more otherdrugs, a pharmaceutical composition in unit dosage form containing suchother drugs and the compound of the present disclosure, i.e., a fixeddose compound, is preferred. However, the combination therapy may alsoinclude therapies in which the compound of this disclosure and one ormore other drugs are administered on different overlapping schedules oreven non-overlapping schedules. It is also contemplated that situationswill arise that when used in combination with one or more other activeingredients, the compounds of the present disclosure and the otheractive ingredients may be used in lower doses than when each is usedsingly.

Dog Pemphigus Foliaceus Study

A 30 kg Doberman dog with a characteristic first presentation ofpemphigus folliaceus on the nose and paws was administered an oral doseof 500 mg daily of the BTK inhibitor(R,E)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrileinstead of the usual treatment for pemphigus of high dosecorticosteroids (typically 1-2 mg/kg). This dose resulted in a level ofBTK occupancy 24 hours after each dose of approximately 70% as confirmedby blood taken 24 hours after the first dose.

The dog responded clinically to the drug as a monotherapy within threedays, with improved eating and ambulation noted by the owner. At the oneweek follow up visit both owner and observing veterinarian reportedimproved general health and commencement of pemphigus lesion healing.The observing veterinarian commented that the improvement was “just likewith corticosteroids” and recommended that corticosteroid therapy didnot need to be commenced. No well-known corticosteroid-like adverseeffects in canines, such as polyuria, polydipsia, polyphagia or weightgain, were noted.

After two weeks of treatment, the general health of the dog wasexcellent and skin lesions continued to improve. By four weeks, skinlesions had completely healed (see FIGS. 1A, 1B, 2A, and 2B).

The surprising conclusion of this experiment is that adequate doses of aBTK inhibitor are effective and safe as the acute treatment forpemphigus folliaceus in a dog, replacing the need for corticosteroidtherapy.

As shown in Table 3, dog PF and human PV share many similarcharacteristics that make generalization of treatment effects for humandisease from observations of the dog disease credible.

TABLE 3 Comparison of dog pemphigus foliaceus (PF) and human pemphigusvulgaris (PV) Naturally occurring autoimmune blistering disease Dog PFHuman PV Autoantigens to epidermal proteins ✓ ✓ Never resolvesspontaneously ✓ ✓ Mainstay of treatment high dose corticosteroids ✓ ✓Early disease response to corticosteroids 1-2 ✓ ✓ weeks Full diseasecontrol with corticosteroids takes ✓ ✓ 4-12 weeks Relapses withoutmaintenance treatment ✓ ✓ High mortality in first year, partly presumeddue ✓ ✓ to high dose corticosteroids

In addition, the ability of (R,E)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrileto rapidly control dog PF suggests that adequate doses of a BTKinhibitor can replace corticosteroids not just in human PV but in otherdiseases where corticosteroids are used acutely.

1-15. (canceled)
 16. A method of treating pemphigus vulgaris orpemphigus foliaceus in a mammal in need thereof comprising administeringto the mammal a therapeutically effective amount of a BTK inhibitor(R,E)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile,wherein the mammal is not a human.
 17. The method of claim 16, whereinthe mammal is a dog.
 18. The method of claim 16, wherein the mammal is acat.
 19. The method of claim 16, further comprising administering theBTK inhibitor in combination with a noncorticosteroidal immunosupressiveand/or anti-inflammatory agent.
 20. The method of claim 19, wherein thenoncorticosteroidal immunosuppressive and/or anti-inflammatory agent ischosen from anti-CD20 antibody, anti-TNF antibody, anti-IL6 agent,anti-IL17 agent, and abatacept.
 21. The method of claim 19, wherein thenoncorticosteroidal immunosuppressive and/or anti-inflammatory agent ischosen from rituximab, tositumomab, veltuzumab, obinutuzumab, Enbrel,and ofatumumab, or a biosimilar version thereof.
 22. A method ofeliminating or reducing a therapeutic dose of a corticosteroid therapyused in the treatment of pemphigus vulgaris or pemphigus foliaceus in amammal in need thereof, wherein the mammal is not a human and thecorticosteroid therapy is used as the first or second line in chronicmaintenance therapy, comprising administering to the mammal atherapeutically effective amount of a BTK inhibitor(R,E)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.23. The method of claim 22, wherein the mammal is a dog.
 24. The methodof claim 22, wherein the mammal is a cat.
 25. The method of claim 22,further comprising administering the BTK inhibitor in combination with anoncorticosteroidal immunosupressive and/or anti-inflammatory agent. 26.The method of claim 25, wherein the noncorticosteroidalimmunosuppressive and/or anti-inflammatory agent is chosen fromanti-CD20 antibody, anti-TNF antibody, anti-IL6 agent, anti-IL17 agent,and abatacept.
 27. The method of claim 25, wherein thenoncorticosteroidal immunosuppressive and/or anti-inflammatory agent ischosen from rituximab, tositumomab, veltuzumab, obinutuzumab, Enbrel,and ofatumumab, or a biosimilar version thereof.
 28. The method of claim22, wherein the BTK inhibitor is used in place of the corticosteroidtherapy.
 29. The method of claim 22, wherein the BTK inhibitor is usedin combination with the corticosteroid therapy.
 30. A method of treatingacute flares of pemphigus vulgaris or pemphigus foliaceus in a mammal inneed thereof, wherein the mammal is not a human and a corticosteroidtherapy is used as the first or second line in chronic maintenancetherapy, comprising administering to the mammal a therapeuticallyeffective amount of a BTK inhibitor(R,E)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile.31. The method of claim 30, wherein the mammal is a dog.
 32. The methodof claim 30, wherein the mammal is a cat.
 33. The method of claim 30,further comprising administering the BTK inhibitor in combination with anoncorticosteroidal immunosupressive and/or anti-inflammatory agent. 34.The method of claim 33, wherein the noncorticosteroidalimmunosuppressive and/or anti-inflammatory agent is chosen fromanti-CD20 antibody, anti-TNF antibody, anti-IL6 agent, anti-IL17 agent,and abatacept.
 35. The method of claim 33, wherein thenoncorticosteroidal immunosuppressive and/or anti-inflammatory agent ischosen from rituximab, tositumomab, veltuzumab, obinutuzumab, Enbrel,and ofatumumab, or a biosimilar version thereof.
 36. The method of claim30, wherein the BTK inhibitor is used in place of the corticosteroidtherapy.
 37. The method of claim 30, wherein the BTK inhibitor is usedin combination with the corticosteroid therapy.